Gamma-tocotrienol has demonstrated anti-proliferative effect on
breast cancer (BCa) cells, but mechanisms involved are largely unknown. This study aimed at deciphering the molecular pathways responsible for its activity. Our results showed that treatment of BCa cells with
gamma-tocotrienol resulted in induction of apoptosis as evidenced by activation of pro-
caspases, accumulation of sub-G1 cells and
DNA fragmentations. Examination of the pro-survival genes revealed that the
gamma-tocotrienol-induced cell death was associated with suppression of Id1 and
NF-kappaB through modulation of their upstream regulators (Src, Smad1/5/8, Fak and LOX). Meanwhile,
gamma-tocotrienol treatment also resulted in the induction of JNK signaling pathway and inhibition of JNK activity by specific inhibitor partially blocked the effect of
gamma-tocotrienol. Furthermore, synergistic effect was observed when cells were co-treated with
gamma-tocotrienol and
Docetaxel. Interestingly, in cells that treated with
gamma-tocotrienol,
alpha-tocopherol or beta-aminoproprionitrile were found to partially restore Id1 expression. Meanwhile, this restoration of Id1 was found to protect the cells from
gamma-tocotrienol induced apoptosis. Consistent outcome was observed in cells ectopically transfected with the Id-1 gene. Our results suggested that the anti-proliferative and chemosensitization effect of
gamma-tocotrienol on BCa cells may be mediated through downregulation of Id1
protein.